Digestive Diseases and Sciences, Vol. 49, Nos. 7/8 (August 2004), pp. 1109–1115 ( C  2004) Cellular Mucosal Defense Is Attenuated with Chronicity of Helicobacter pylori Infection GEOFFREY M. MATTHEWS, MSc,*† DAVID TIVEY, PhD,‡ ADRIAN G. CUMMINS, MD, PhD, FRACP,§ and ROSS N. BUTLER, PhD* This study assessed the mucosal antioxidant response during acute (mouse) and chronic (adult human) H. pylori infection and following N -acetylcysteine administration. Antral biopsies were obtained from 44 patients (16 infected, 28 noninfected). Sixty-nine mice were sacrificed after 1 (n = 25), 4 (n = 28), or 6 (n = 16) months of infection. A further 29 mice received N -acetylcysteine or water (n = 21) for 14 days following 2.5 weeks of infection. Infected patients showed simi- lar glutathione levels and G6PDH activity to noninfected subjects ( P > 0.05). Myeloperoxidase activity was higher in infected patients ( P < 0.05). In infected mice, glutathione levels and G6PDH activity were elevated at all time points up 6 months of infection ( P < 0.05). Myeloperoxidase ac- tivity was increased in infected mice after 1 and 4 months ( P < 0.05) but not at 6 months of infection ( P > 0.05). N -Acetylcysteine reduced all three parameters in H. pylori-infected mice ( P < 0.05). These results suggest an up-regulation of the antioxidant defense system during H. pylori infection in the mouse but not in humans. N -Acetylcysteine reduces the response during infection possibly by lowering the oxidant load. KEY WORDS: Helicobacter pylori; oxidative pentose pathway; glutathione; myeloperoxidase. It is currently accepted that Helicobacter pylori infection is acquired in childhood (1), however, little is known of the natural history of the infection with respect to the length of infection and the role of antioxidants in preventing or ameliorating associated gastritis. H. pylori infection is as- sociated with a neutrophil predominant inflammation of the mucosa resulting in mucosal cell damage (2–6). The exact mechanisms mediating the mucosal injury during H. pylori infection are not fully understood, however, there is evidence of a role for reactive oxygen species (ROS) (7–9). Activated neutrophils generate ROS and myeloperoxidase Manuscript accepted March 3, 2004. From the *Gastroenterology Department, Women’s and Children’s Hospital, North Adelaide, and †Physiology Department, University of Adelaide, South Australia, ‡Department of Animal Science, Univer- sity of Adelaide, South Australia, and §Department of Gastroenterology and Hepatology, The Queen Elizabeth Hospital, Woodville South, South Australia. Address for reprint requests: Geoff Matthews, MSc, Gastroenterology Department, Women’s and Children’s Hospital, 72 King William Road, North Adelaide, South Australia 5006; matthewsg@mail.wch.sa.gov.au. and these are associated with gastritis and peptic ulcer dis- ease (8–11). Accordingly, the generation and maintenance of intracellular antioxidants to counteract the ROS load is likely to modify the host response to this bacterium. Intracellular glutathione is probably the most impor- tant antioxidant and the glandular mucosa of the stomach is known to have one of the highest glutathione levels in the body (7, 12, 13). Exposure of glutathione to ROS oxi- dises it to form glutathione disulfide that is reduced to glu- tathione by glutathione reductase. The NADPH reducing equivalents utilized in the glutathione reductase–catalyzed step are principally produced by glucose-6-phosphate de- hydrogenase (G6PDH), the rate-limiting enzyme of the oxidative pentose phosphate pathway (OPP) (14, 15). Hence, the level of glutathione in gastric mucosa is mainly regulated by the activity of G6PDH. However, the role of the OPP in the host mucosal response to H. pylori infection has not been assessed. Previous studies have reported changes to mucosal glutathione during H. pylori infection in adult humans Digestive Diseases and Sciences, Vol. 49, Nos. 7/8 (August 2004) 1109 0163-2116/04/0800-1109/0 C  2004 Springer Science+Business Media, Inc.